Back to resultsSafety and Efficacy of Mipomersen in Patients With Severe Hypercholesterolemia on a Maximally Tolerated Lipid-Lowering Regimen and Who Are Not on Apheresis
Primary Purpose
Hypercholesterolemia, Coronary Heart Disease
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Mipomersen
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Hypercholesterolemia
Eligibility Criteria
Inclusion Criteria:
Fasting LDL-C ≥200 mg/dL (5.1 mmol/L) at screening and the presence of at least 1 of the following criteria:
- Myocardial infarction (MI)
- Percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG)
- Coronary artery disease documented by angiography or any other accepted imaging technique
- Positive exercise test (≥1 mm ST-depression at maximal exercise or test terminated because of angina) or a perfusion defect (e.g., thallium or single photon emission computed tomography)
- Other clinical atherosclerotic diseases: peripheral artery disease, symptomatic carotid artery disease, abdominal aortic aneurysm
- Or, if alternative above were not met, fasting LDL-C ≥300 mg/dL (7.8 mmol/L)
- On stable, maximally tolerated statin therapy for 8 weeks
- On stable, medication from an additional class of hypolipidemic agents for 8 weeks.
- On stable, low fat diet for 12 weeks
- Stable weight for 6 weeks
Exclusion Criteria:
- Significant health problems in the recent past including heart attack, stroke, coronary syndrome, unstable angina, heart failure, significant arrhythmia, hypertension, blood disorders, liver disease, cancer, digestive disorders, Type I diabetes, or uncontrolled Type II diabetes
- Apheresis within 3 months prior to Screening or expected to start apheresis during the treatment phase
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Placebo Comparator
Experimental
Arm Label
Placebo
Mipomersen
Arm Description
Weekly subcutaneous injections for 26 weeks
200 mg weekly subcutaneous injections for 26 weeks
Outcomes
Primary Outcome Measures
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Primary Efficacy Time Point
LDL-C was measured in mg/dL. Samples were taken following an overnight fast. For patients with triglycerides <400 mg/dL, LDL-C was obtained using Friedewald's calculation; and for patients with triglycerides >=400 mg/dL, LDL-C was directly measured by the central laboratory using ultracentrifugation. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
LDL-C at Baseline and the Primary Efficacy Time Point (PET)
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Secondary Outcome Measures
Percent Change From Baseline in Apolipoprotein B (Apo-B) at Primary Efficacy Time Point
Apo-B was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Apo-B at Baseline and the Primary Efficacy Time Point (PET)
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Percentage Change From Baseline in Total Cholesterol at Primary Efficacy Time Point (PET)
Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Total Cholesterol at Baseline and the Primary Efficacy Time Point (PET)
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Percentage Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Primary Efficacy Time Point (PET)
Non-HDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Non-HDL-C at Baseline and the Primary Efficacy Time Point (PET)
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Full Information
NCT ID
NCT00794664
First Posted
November 19, 2008
Last Updated
August 1, 2016
Sponsor
Kastle Therapeutics, LLC
Collaborators
Ionis Pharmaceuticals, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT00794664
Brief Title
Safety and Efficacy of Mipomersen in Patients With Severe Hypercholesterolemia on a Maximally Tolerated Lipid-Lowering Regimen and Who Are Not on Apheresis
Official Title
A Prospective Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of Mipomersen in Patients With Severe Hypercholesterolemia on a Maximally Tolerated Lipid-Lowering Regimen and Who Are Not on Apheresis
Study Type
Interventional
2. Study Status
Record Verification Date
August 2016
Overall Recruitment Status
Completed
Study Start Date
January 2009 (undefined)
Primary Completion Date
May 2010 (Actual)
Study Completion Date
October 2010 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Kastle Therapeutics, LLC
Collaborators
Ionis Pharmaceuticals, Inc.
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of the study is to evaluate the safety and efficacy of dosing with mipomersen for 26 weeks in treating severely hypercholesterolemic patients who are on a maximally tolerated lipid-lowering regimen and who are not on apheresis.
Detailed Description
Hypercholesterolemia is characterized by markedly elevated low density lipoproteins (LDL). Elevated LDL is a major risk factor for coronary heart disease (CHD).
Mipomersen is an antisense drug that reduces a protein in the liver cells called apolipoprotein B (Apo-B). Apo-B plays a role in producing low density lipoprotein cholesterol (LDL-C) (the "bad" cholesterol) and moving it from the liver to one's bloodstream. High LDL-C is an independent risk factor for the development of coronary heart disease (CHD) or other diseases of blood vessels. It has been shown that lowering LDL-C reduces the risk of heart attacks and other major adverse cardiovascular events. The purpose of this study is to determine whether mipomersen safely and effectively lowers LDL-C in severely hypercholesterolemic patients who are on a maximally tolerated lipid-lowering regimen and who are not on apheresis.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypercholesterolemia, Coronary Heart Disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
58 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Weekly subcutaneous injections for 26 weeks
Arm Title
Mipomersen
Arm Type
Experimental
Arm Description
200 mg weekly subcutaneous injections for 26 weeks
Intervention Type
Drug
Intervention Name(s)
Mipomersen
Other Intervention Name(s)
ISIS 301012, Mipomersen sodium, Kynamro™
Intervention Description
200 mg (1 mL), weekly subcutaneous injections for 26 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
1 mL weekly subcutaneous injections for 26 weeks
Primary Outcome Measure Information:
Title
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Primary Efficacy Time Point
Description
LDL-C was measured in mg/dL. Samples were taken following an overnight fast. For patients with triglycerides <400 mg/dL, LDL-C was obtained using Friedewald's calculation; and for patients with triglycerides >=400 mg/dL, LDL-C was directly measured by the central laboratory using ultracentrifugation. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
LDL-C at Baseline and the Primary Efficacy Time Point (PET)
Description
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Secondary Outcome Measure Information:
Title
Percent Change From Baseline in Apolipoprotein B (Apo-B) at Primary Efficacy Time Point
Description
Apo-B was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
Apo-B at Baseline and the Primary Efficacy Time Point (PET)
Description
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
Percentage Change From Baseline in Total Cholesterol at Primary Efficacy Time Point (PET)
Description
Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
Total Cholesterol at Baseline and the Primary Efficacy Time Point (PET)
Description
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
Percentage Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Primary Efficacy Time Point (PET)
Description
Non-HDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
Non-HDL-C at Baseline and the Primary Efficacy Time Point (PET)
Description
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Other Pre-specified Outcome Measures:
Title
Percentage Change From Baseline in Triglycerides at Primary Efficacy Time Point (PET)
Description
Triglycerides were measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
Triglycerides at Baseline and the Primary Efficacy Time Point (PET)
Description
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
Percentage Change From Baseline in Lipoprotein(a) at Primary Efficacy Time Point (PET)
Description
Lipoprotein(a) was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
Lipoprotein(a) at Baseline and the Primary Efficacy Time Point (PET)
Description
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
Percentage Change From Baseline in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) at Primary Efficacy Time Point (PET)
Description
VLDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
VLDL-C at Baseline and the Primary Efficacy Time Point (PET)
Description
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
Change From Baseline in Ratio of Low-density Lipoprotein Cholesterol (LDL-C) to High-density Lipoprotein Cholesterol (HDL-C) at Primary Efficacy Time Point (PET)
Description
LDL-C and HDL-C were measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
Ratio of LDL-C to HDL-C at Baseline and the Primary Efficacy Time Point (PET)
Description
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
Percent Change From Baseline in Apolipoprotein A1 (Apo-A1) at Primary Efficacy Time Point (PET)
Description
Apo-A1 was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
Apo-A1 at Baseline and the Primary Efficacy Time Point (PET)
Description
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
Percentage Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Primary Efficacy Time Point (PET)
Description
HDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Title
HDL-C at Baseline and the Primary Efficacy Time Point (PET)
Description
The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Time Frame
Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Fasting LDL-C ≥200 mg/dL (5.1 mmol/L) at screening and the presence of at least 1 of the following criteria:
Myocardial infarction (MI)
Percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG)
Coronary artery disease documented by angiography or any other accepted imaging technique
Positive exercise test (≥1 mm ST-depression at maximal exercise or test terminated because of angina) or a perfusion defect (e.g., thallium or single photon emission computed tomography)
Other clinical atherosclerotic diseases: peripheral artery disease, symptomatic carotid artery disease, abdominal aortic aneurysm
Or, if alternative above were not met, fasting LDL-C ≥300 mg/dL (7.8 mmol/L)
On stable, maximally tolerated statin therapy for 8 weeks
On stable, medication from an additional class of hypolipidemic agents for 8 weeks.
On stable, low fat diet for 12 weeks
Stable weight for 6 weeks
Exclusion Criteria:
Significant health problems in the recent past including heart attack, stroke, coronary syndrome, unstable angina, heart failure, significant arrhythmia, hypertension, blood disorders, liver disease, cancer, digestive disorders, Type I diabetes, or uncontrolled Type II diabetes
Apheresis within 3 months prior to Screening or expected to start apheresis during the treatment phase
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Genzyme, a Sanofi Company
Official's Role
Study Director
Facility Information:
City
Jupiter
State/Province
Florida
ZIP/Postal Code
33458
Country
United States
City
Winter Park
State/Province
Florida
ZIP/Postal Code
32792
Country
United States
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30338
Country
United States
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
City
St Louis
State/Province
Missouri
ZIP/Postal Code
63104
Country
United States
City
Concord
State/Province
New Hampshire
ZIP/Postal Code
03301
Country
United States
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45212
Country
United States
City
Aiken
State/Province
South Carolina
ZIP/Postal Code
29801
Country
United States
City
Winnipeg
State/Province
Manitoba
ZIP/Postal Code
R3A 1M5
Country
Canada
City
Chicoutimi
State/Province
Quebec
ZIP/Postal Code
G7H 5H6
Country
Canada
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H1T 1C8
Country
Canada
City
Hardec Kralove
ZIP/Postal Code
500 05
Country
Czech Republic
City
Pilsen
ZIP/Postal Code
305 99
Country
Czech Republic
City
Praha
ZIP/Postal Code
128 08
Country
Czech Republic
City
Uherske Hradiste
ZIP/Postal Code
686 68
Country
Czech Republic
City
Berlin
ZIP/Postal Code
13353
Country
Germany
City
Freiburg
ZIP/Postal Code
79106
Country
Germany
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
City
Koln (Lindenthal)
ZIP/Postal Code
50937
Country
Germany
City
Cape Town
ZIP/Postal Code
7500
Country
South Africa
City
Cape Town
ZIP/Postal Code
7925
Country
South Africa
City
Gauteng
ZIP/Postal Code
0157
Country
South Africa
City
Pretoria
ZIP/Postal Code
0002
Country
South Africa
City
Guildford
State/Province
Surrey
ZIP/Postal Code
GU2 7XX
Country
United Kingdom
City
London
ZIP/Postal Code
SE1 7EH
Country
United Kingdom
City
Manchester
ZIP/Postal Code
MI3 9WL
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
23152839
Citation
McGowan MP, Tardif JC, Ceska R, Burgess LJ, Soran H, Gouni-Berthold I, Wagener G, Chasan-Taber S. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PLoS One. 2012;7(11):e49006. doi: 10.1371/journal.pone.0049006. Epub 2012 Nov 13.
Results Reference
result
PubMed Identifier
27578134
Citation
Duell PB, Santos RD, Kirwan BA, Witztum JL, Tsimikas S, Kastelein JJP. Long-term mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia. J Clin Lipidol. 2016 Jul-Aug;10(4):1011-1021. doi: 10.1016/j.jacl.2016.04.013. Epub 2016 May 9.
Results Reference
derived
PubMed Identifier
25614280
Citation
Santos RD, Raal FJ, Catapano AL, Witztum JL, Steinhagen-Thiessen E, Tsimikas S. Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials. Arterioscler Thromb Vasc Biol. 2015 Mar;35(3):689-99. doi: 10.1161/ATVBAHA.114.304549. Epub 2015 Jan 22.
Results Reference
derived
Learn more about this trial
Safety and Efficacy of Mipomersen in Patients With Severe Hypercholesterolemia on a Maximally Tolerated Lipid-Lowering Regimen and Who Are Not on Apheresis
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